This Application is the National Stage of International Application Serial No. PCT/JP98/04837, filed Oct. 26, 1998.
The present invention relates to an agent for antagonizing adenosine at adenosine A3 receptors and a novel thiazole compound having a superior antagonistic activity at adenosine A3 receptor.
As subtypes of adenosine receptors, A1, A2a, A2b and A3 are known. Adenosine induces bronchial constriction in asthma patients, while theophylline, which is known as an antiasthmatic, antagonizes adenosine. Recently several reports showed that activation of adenosine A3 receptors in rats promotes degranulation of mast cells [Journal of Biological Chemistry, 268, 16887-16890 (1993)], that adenosine A3 receptors exist on peripheral blood eosinophils and that the stimulation of adenosine A3 receptors activates phospholipase C and elevates intracellular calcium [Blood, 88, 3569-3574 (1996)].
Currently, as selective A3 adenosine receptor antagonists, xanthine derivatives are reported in GB-A-2288733 and WO 95/11681, and the following compounds are reported in Journal of Medicinal Chemistry, 40, 2596-2608(1997). 
The following thiazole compounds are known.
1) A thiazole derivative of the formula: 
wherein R1 represents i) cycloalkyl, ii) cyclic amino, iii) amino which may be substituted by 1 or 2 substituents selected from the group consisting of lower alkyl, phenyl, acetyl and lower alkoxycarbonylacetyl, iv) alkyl which may be substituted by a substituent selected from the group consisting of hydroxy, carboxy and lower alkoxycarbonyl or v) phenyl which may be substituted by a substituent selected from the group consisting of carboxy, 2-carboxyethenyl and 2-carboxy-1-propenyl; R2 represents pyridyl which may be substituted by a lower alkyl; and R3 represents phenyl which may be substituted by a substituent selected from the group consisting of lower alkoxy, lower alkyl, hydroxy, halogen and methylenedioxy, or a salt thereof, which has analgesic, anti-pyretic, anti-inflammatory, anti-ulcer, thromboxane A2 (TXA2) synthetase inhibitory and platelet aggregation inhibiting actions (JP-A-60-58981).
2) A 1,3-thiazole derivative of the formula: 
wherein R1 represents an optionally substituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclic group having carbon as the attachment point or amino; R2 represents pyridyl which may be substituted by an alkyl; and R3 represents phenyl which may be substituted, or a salt thereof, which has analgesic, anti-pyretic, anti-inflammatory, anti-ulcer, thromboxane A2 (TXA2) synthetase inhibitory and platelet aggregation inhibiting actions (JP-A-61-10580).
3) A 1,3-thiazole derivative of the formula: 
wherein R1 represents an optionally substituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclic group having carbon as the attachment point or amino; R2 represents pyridyl which may be substituted by an alkyl; and R3 represents aryl which may be substituted, or a salt thereof, which has analgesic, anti-pyretic, anti-inflammatory, anti-ulcer, thromboxane A2 (TXA2) synthetase inhibitory and platelet aggregation inhibiting actions (U.S. Pat. No. 4,612,321).
4) A compound of the formula: 
wherein R1 is an optionally substituted phenyl, R2 is C1-6 alkyl or (CH2)nAr, n is 0-2, Ar is an optionally substituted phenyl, R3 is hydrogen or C1-4 alkyl, R4 is hydrogen, C1-4 alkyl, etc, R5 is hydrogen or C1-4 alkyl, R6 is hydrogen, C1-4 alkyl, etc, or salt thereof, which has an activity of inhibiting gastric acid secretion (JP-A-07-503023, WO 93/15071).
5) A compound of the formula: 
wherein R1 is pyridyl, etc, R2 is phenyl, etc, R3 and R4 are hydrogen or methyl, R5 is methyl, etc, R6 is hydrogen or methyl, etc, or a salt thereof, which is useful as anti-inflammatory and anti-allergic agents (DE-A-3601411).
6) A compound of the formula: 
wherein R1 is lower alkyl substituted by halogen, R2 is pyridyl, etc, R3 is phenyl, etc, or a salt thereof, which has anti-inflammatory, antipyretic, analgesic and anti-allergic activities (JP-A-5-70446).
From the prior art described above, it is thought that adenosine causes asthma through its binding to adenosine A3 receptor, therefore A3 adenosine receptor antagonists are expected to become a new type of antiasthma drug. Accordingly, an agent for antagonizing adenosine at adenosine A3 receptors which has potent antagonistic activity, good bioavailability upon administration and good metabolical stability are expected to have potent therapeutic effects for asthma, inflammation, Addison""s diseases, autoallergic hemolytic anemia, Crohn""s diseases, psoriasis, rheumatism and diabetes. However, as a prophylactic and therapeutic agent for adenosine A3 receptor-related diseases, no good agents for antagonising adenosine at gadenosine A3 receptors are known in terms of potency, safety, bioavailability, and metabolic""stability. Therefore a good agent for antagonising adenosine at adenosine A3 receptor is expected to be developed.
We, the present inventors, have studied various compounds having an antagonistic activity at adenosine A3 receptors, and as a result, have found for the first time that a 1,3-azole compound substituted on the 4- or 5-position, or both, by a pyridyl which may be substituted (hereinafter sometimes referred to briefly as compound (I)], has an unexpected, excellent selective affinity to adenosine A3 receptor, antagonistic activity at adenosine A3 receptor and high stability, and is therefore satisfactory as a medicine.
Compound (I) comprises, for example, a compound of the formula: 
wherein R1 represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an amino which may be substituted or an acyl;
at least one of R2 and R3 represents a hydrogen atom, a pyridyl which may be substituted or an aromatic hydrocarbon group which may be substituted, and the other represents a pyridyl which may be substituted; and
X represents a sulfur atom which may be oxidized, an oxygen atom or a group of the formula: NR4 wherein R4 represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl;
or a salt thereof, which may be N-oxidized [hereinafter sometimes referred to briefly as compound (Ia)], and a novel compound of the formula: 
wherein R1a represents (i) an aromatic heterocyclic group which may be substituted, (ii) an amino which may be substituted by substituent(s) selected from the group consisting of a substituted carbonyl and a hydrocarbon group which may be substituted, (iii) a cyclic amino which may be substituted or (iv) an acyl;
R2a represents an aromatic hydrocarbon group which may be substituted; and
R3a represents a pyridyl which may be substituted, or a salt thereof [hereinafter sometimes referred to briefly as compound (Ib)] being within the scope of compound (Ia).
On the basis of these findings, the inventors have completed the present invention.
Specifically, the present invention relates to:
(1) A pharmaceutical composition for antagonizing adenosine at adenosine A3 receptors which comprises compound (I);
(2) a composition of the above (1), wherein the 1,3-azole compound is compound (Ia);
(3) a composition of the above (2), wherein R1 is
(i) a hydrogen atom,
(ii) a C1-8 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl or C7-16 aralkyl group which may be substituted by 1 to 5 substituents,
(iii) a 5- to 14-membered heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, which group may be substituted by 1 to 5 substituents,
(iv) an amino which may be substituted by 1 or 2 substituents selected from the group consisting of
(a) a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl or C7-16 aralkyl group which may be substituted by 1 to 5 substituents,
(b) a C1-6 alkylidene group which may be substituted by 1 to 5 substituents,
(c) a 5- to 14-membered heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, which group may be substituted by 1 to 5 substituents, and
(d) an acyl of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5, xe2x80x94(Cxe2x95x90O)xe2x80x94OR5, xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6, xe2x80x94(Cxe2x95x90S)xe2x80x94NHR5 or xe2x80x94SO2xe2x80x94R7 wherein R5 is (ixe2x80x2) a hydrogen atom, (iixe2x80x2) a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl or C7-16 aralkyl group which may be substituted by 1 to 5 substituents or (iiixe2x80x2) a 5- to 14-membered heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, which group may be substituted by 1 to 5 substituents; R6 is a hydrogen atom or C1-6 alkyl; and R7 is (ixe2x80x2) a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl or C7-16 aralkyl group which may be substituted by 1 to 5 substituents or (iixe2x80x2) a 5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, which group may be substituted by 1 to 5 substituents,
(v) a 5- to 7-membered non-aromatic cyclic amino optionally containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms and at least one nitrogen atom, which may be substituted by 1 to 3 substituents selected from the group consisting of C1-6 alkyl, C6-14 aryl, C1-6 alkyl-carbonyl, 5- to 10-membered aromatic heterocyclic group and oxo, or
(vi) an acyl of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5, xe2x80x94(Cxe2x95x90O)xe2x80x94OR5, xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6, xe2x80x94(Cxe2x95x90S)xe2x80x94NHR5 or xe2x80x94SO2xe2x80x94R7 wherein each symbol is as defined above;
at least one of R2 and R3 is
(i) a hydrogen atom,
(ii) a pyridyl which may be substituted by 1 to 5 substituents or
(iii) a C6-14 aryl which may be substituted by 1 to 5 substituents in which a substituent can form, together with a neighboring substituent, a 4- to 7-membered non-aromatic carbocyclic ring;
and the other is a pyridyl which may be substituted by 1 to 5 substituents; and
X is a sulfur atom which may be oxidized, an oxygen atom or a group of the formula: NR4 wherein R4 is (i) a hydrogen atom, (ii) a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl or C7-16 aralkyl group which may be substituted by 1 to 5 substituents or (iii) an acyl of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5; xe2x80x94(Cxe2x95x90O)xe2x80x94OR5, xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6, xe2x80x94(Cxe2x95x90S)xe2x80x94NHR5 or xe2x80x94SO2xe2x80x94R7 wherein each symbol is as defined above, wherein the above xe2x80x9csubstituentsxe2x80x9d are selected from the group consisting of (1) halogen atoms, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) optionally halogenated C1-6 alkyl, (6) optionally halogenated C2-6 alkenyl, (7) carboxy C2-6 alkenyl, (8) optionally halogenated C2-6 alkynyl, (9) optionally halogenated C3-6 cycloalkyl, (10) C6-14 aryl, (11) optionally halogenated C1-8 alkoxy, (12) C1-6 alkoxy-carbonyl-C1-6 alkoxy, (13) hydroxy, (14) C6-14 aryloxy, (15) C7-16 aralkyloxy,(16) mercapto, (17) optionally halogenated C1-6 alkylthio, (18) C6-14 arylthio, (19) C7-16 aralkylthio, (20) amino, (21) mono-C1-6 alkylamino, (22) mono-C6-14 arylamino, (23) di-C1-6 alkylamino, (24) di-C6-14 arylamino, (25) formyl, (26) carboxy, (27) C1-6 alkyl-carbonyl, (28) C3-6 cycloalkyl-carbonyl, (29) C1-6 alkoxy-carbonyl, (30) C6-14 aryl-carbonyl, (31) C7-16 aralkyl-carbonyl, (32) C6-14 aryloxy-carbonyl, (33) C7-16 aralkyloxy-carbonyl, (34) 5- or 6-membered heterocycle carbonyl, (35) carbamoyl, (36) mono-C1-6 alkyl-carbamoyl, (37) di-C1-6 alkyl-carbamoyl, (38) C6-14 aryl-carbamoyl, (39) 5- or 6-membered heterocycle carbamoyl, (40) C1-6 alkylsulfonyl, (41) C6-14 arylsulfonyl, (42) formylamino, (43) C1-6 alkyl-carbonylamino, (44) C6-14 aryl-carbonylamino, (45) C1-6 alkoxy-carbonylamino, (46) C1-6 alkylsulfonylamino, (47) C6-14 arylsulfonylamino, (48) C1-6 alkyl-carbonyloxy, (49) C6-14 aryl-carbonyloxy, (50) C1-6 alkoxy-carbonyloxy, (51) mono-C1-6 alkyl-carbamoyloxy, (52) di-Ci6 alkyl-carbamoyloxy, (53) C6-14 aryl-carbamoyloxy, (54) nicotinoyloxy, (55) 5- to 7-membered saturated cyclic amino which may be substituted by 1 to 3 substituents selected from the group consisting of C1-6 alkyl, C6-14 aryl, C1-6 alkyl-carbonyl, 5- to 10-membered aromatic heterocyclic group and oxo, (56) 5- to 10-membered aromatic heterocyclic group and (57) sulfo;
(4) a composition of the above (2), wherein R1 is an amino which may be substituted;
(5) a composition of the above (3), wherein R1 is an amino which may be substituted by 1 or 2 acyl of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5, xe2x80x94(Cxe2x95x90O)xe2x80x94OR5, xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6, xe2x80x94(Cxe2x95x90S)xe2x80x94NHR5 or xe2x80x94SO2xe2x80x94R7;
(6) a composition of the above (3), wherein R1 is an amino which may be substituted by 1 or 2 acyl of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5 or xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6;
(7) a composition of the above (3), wherein R1 is a 5- to 7-membered non-aromatic cyclic amino optionally containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms and at least one nitrogen atom, which may be substituted by 1 to 3 substituents selected from the group consisting of C1-6 alkyl, C6-14 aryl, C1-6 alkyl-carbonyl, 5- to 10-membered aromatic heterocyclic group and oxo;
(8) a composition of the above (2), wherein X is S;
(9) a composition of the above (2), wherein R2 is a pyridyl which may be substituted;
(10) a composition of the above (2), wherein R3 is a C6-14 aryl which may be substituted;
(11) a composition of the above (3), wherein R1 is an amino which may be substituted by 1 or 2 acyl of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5 or xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6;
R2 is a pyridyl which may be substituted by 1 to 5 C1-6 alkyl;
R3 is a C6-14 aryl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy and carboxy; and
X is S;
(12) a composition of the above (2), wherein R1 is
(i) a C1-8 alkyl, C3-6 cycloalkyl or C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, optionally halogenated C1-6 alkyl, carboxy C2-6 alkenyl, optionally halogenated C1-6 alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkoxy, hydroxy, amino, mono-C-1-6 alkylamino, carboxy, C1-6 alkoxy-carbonyl, mono-C1-6 alkyl-carbamoyl and C6-14 aryl-carbonylamino,
(ii) a 5-membered heterocyclic group,
(iii) an amino which may be substituted by 1 or 2 substituents selected from the group consisting of (1) C1-6 alkyl, (2) C6-14 aryl, (3) C7-16 aralkyl,(4) 6-membered heterocyclic group, (5) a C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C1-6 alkyl-carbamoyl or 5- or 6-membered heterocycle carbonyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C1-6 alkyl, C1-6 alkoxy, carboxy and C1-6 alkoxy-carbonyl, and (6) di-C1-6 alkylamino-C1-6 alkylidene,
(iv) a 5- or 6-membered non-aromatic cyclic amino which may be substituted by C1-6 alkyl-carbonyl or oxo, or
(v) carboxy;
R2is a pyridyl which may be substituted by 1 to 3 C1-6 alkyl;
R3 is a C6-10 aryl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, optionally halogenated C1-6 alkyl, carboxy C2-6 alkenyl, optionally halogenated C1-8 alkoxy, hydroxy, C7-16 aralkyloxy and C1-6 alkyl-carbonyloxy, in which the alkyl group can form, together with a neighboring alkyl group, a 5-membered non-aromatic carbocyclic ring; and
X is S;
(13) an adenosine A3 receptor antagonist which comprises a 1,3-azole compound substituted on the 4- or 5-position, or both, by a pyridyl which may be substituted;
(14) a composition of the above (1), which is for preventing and/or treating asthma or allergosis;
(15) compound (Ib);
(16) a compound of the above (15), wherein R1a is an amino which may be substituted by 1 or 2 substituents selected from the group consisting of C1-6 alkyl, C1-6 alkyl-carbonyl, C6-14 aryl-carbonyl and C1-6 alkyl-carbamoyl;
R2a is a phenyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, optionally halogenated C1-6 alkyl and optionally halogenated C1-6 alkoxy; and
R3a is a pyridyl;
(17) a process for producing compound (Ib), which comprises reacting a compound of the formula: 
wherein Hal represents halogen atoms and other symbols are as defined above, or a salt thereof with a compound of the formula: 
wherein R1a is as defined above, or a salt thereof, optionally in the presence of a base;
(18) a pharmaceutical composition which comprises compound (Ib);
(19) a composition of the above (18) which is an agent for antagonizing adenosine at adenosine A3 receptors;
(20) a composition of the above (18) which is for preventing and/or treating asthma or allergosis;
(21) a method for preventing and/or treating diseases related to adenosine A3 receptor in mammal, which comprises administering to said mammal an effective amount of a compound of the above (1) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, carrier or diluent; and
(22) use of a compound of the above (1) or a salt thereof for manufacturing a pharmaceutical composition for preventing and/or treating diseases related to adenosine A3 receptor, and so forth.
In this specification, the xe2x80x9cacylxe2x80x9d includes, for example, an acyl of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5, xe2x80x94(Cxe2x95x90O)xe2x80x94OR5, xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6, xe2x80x94(Cxe2x95x90S)xe2x80x94NHR5 or xe2x80x94SO2xe2x80x94R7 wherein R5 represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; R6 represents a hydrogen atom or C1-6 alkyl; and R7 represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.
In the above formulae, the xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R5 includes, for example, an acyclic or cyclic hydrocarbon group such as alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, etc. Among them, C1-16 acyclic or cyclic hydrocarbon group is preferable.
The preferred xe2x80x9calkylxe2x80x9d is for example C1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
The preferred xe2x80x9calkenylxe2x80x9d is for example C2-6 alkenyl such as vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, etc.
The preferred xe2x80x9calkynylxe2x80x9d is for example C2-6 alkynyl such as ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, etc.
The preferred xe2x80x9ccycloalkylxe2x80x9d is for example C3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
The preferred xe2x80x9carylxe2x80x9d is for example C6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.
The preferred xe2x80x9caralkylxe2x80x9d is for example C7-16 aralkyl such as benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.
Examples of the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R5 include halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C1-6 alkyl, optionally halogenated C2-6 alkenyl, carboxy C2-6 alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyl, etc.), optionally halogenated C2-6 alkynyl, optionally halogenated C3-6 cycloalkyl, C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.), optionally halogenated C1-8 alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkoxy (e.g., ethoxycarbonylmethyloxy, etc.), hydroxy, C6-14 aryloxy (e.g., phenyloxy, 1-naphthyloxy, 2-naphthyloxy, etc.), C7-16 aralkyloxy (e.g., benzyloxy, phenethyloxy, etc.), mercapto, optionally halogenated C1-6 alkylthio, C6-14 arylthio (e.g., phenylthio, 1-naphthylthio, 2-naphthylthio, etc.), C7-16 aralkylthio (e.g., benzylthio, phenethylthio, etc.), amino, mono-C1-6 alkylamino (e.g., methylamino, ethylamino, etc.), mono-C6-14 arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino, etc.), di-C6-14 arylamino (e.g., diphenylamino, etc.), formyl, carboxy, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), C3-6 cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C7-16 aralkyl-carbonyl (e.g., phenylacetyl, 3-phenylpropionyl, etc.), C6-14 aryloxy-carbonyl (e.g., phenoxycarbonyl, etc.), C7-16 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-membered heterocycle carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, etc.), carbamoyl, mono-C1-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C1-6 alkyl-carbamoyl (e.g., dimethylcarbamroyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C6-14 aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), 5- or 6-membered heterocycle carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), C6-14 arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), formylamino, C1-6 alkyl-carbonylamino (e.g., acetylamino, etc.), C6-14 aryl-carbonylamino (e.g., benzoylamino, naphthoylamino, etc.), C1-6 alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.), C1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), C6-14 arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), C1-6 alkyl-carbonyloxy (e.g., acetoxy, propionyloxy, etc.), C6-14 aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy, etc.), C1-6 alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C1-6 alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C1-6 alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C6-14 aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy, 5- to 7-membered saturated cyclic amino which may be substituted, 5- to 10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, etc.), sulfo, and so forth.
The xe2x80x9chydrocarbon groupxe2x80x9d may have 1 to 5, preferably 1 to 3 substituents as mentioned above at possible positions of the hydrocarbon group and, when the number of substituents is two or more, those substituents may be the same as or different from one another.
The above-mentioned xe2x80x9coptionally halogenated C1-6 alkylxe2x80x9d includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.). Concretely mentioned is methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.
The above-mentioned xe2x80x9coptionally halogenated C2-6 alkenylxe2x80x9d includes, for example, C2-6 alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.).
The above-mentioned xe2x80x9coptionally halogenated C2-6 alkynylxe2x80x9d includes, for example, C2-6 alkynyl (e.g., 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.).
The above-mentioned xe2x80x9coptionally halogenated C3-6 cycloalkylxe2x80x9d includes, for example, C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.). Concretely mentioned is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4 -dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, etc.
The above-mentioned xe2x80x9coptionally halogenated C1-8 alkoxyxe2x80x9d includes, for example, C1-8 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.). Concretely mentioned is methoxy, difluoromethoxy, trifluoromethoxy,ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.
The above-mentioned xe2x80x9coptionally halogenated C1-6 alkylthioxe2x80x9d includes, for example, C1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.). Concretely mentioned is methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc.
The above-mentioned xe2x80x9c5- to 7-membered saturated cyclic aminoxe2x80x9d of the xe2x80x9c5- to 7-membered saturated cyclic amino which may be substitutedxe2x80x9d includes, for example, 5- to 7-membered saturated cyclic amino optionally containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms and at least one nitrogen atom, such as pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, tetrahydroazepin-1-yl, etc.
The xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9c5- to 7-membered saturated cyclic amino which may be substitutedxe2x80x9d include, for example, 1 to 3 substituents selected from the group consisting of C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.), C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), and 5- to 10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, etc.), oxo, and so forth.
The xe2x80x9cheterocyclic groupxe2x80x9d of the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d for R5 includes, for example, a monovalent group formed by removing an optional hydrogen atom from a 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic ring containing 1 to 4 hetero atoms of 1 or 2 species selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, preferably, (i) a 5- to 14-membered, preferably, 5- to 10-membered aromatic heterocyclic ring, (ii) a 5- to 10-membered non-aromatic heterocyclic ring and (iii) a 7- to 10-membered bridged heterocyclic ring, etc.
The above-mentioned xe2x80x9c5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic ringxe2x80x9d includes, for example, an aromatic heterocyclic ring such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine, etc.; and a ring as formed through condensation of those. rings, preferably a monocyclic ring, with one or more, preferably one or two aromatic rings (e.g., benzene ring, etc.), etc.
The above-mentioned xe2x80x9c5- to 10-membered non-aromatic heterocyclic ringxe2x80x9d includes, for example, pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dioxazole, oxadiazoline, oxathiazole, thiadiazoline, triazoline, thiadiazole, dithiazole, etc.
The above-mentioned xe2x80x9c7- to 10-membered bridged heterocyclic ringxe2x80x9d includes, for example, quinuclidine, 7-azabicyclo[2.2.1]heptane, etc.
Preferable examples of the xe2x80x9cheterocyclic groupxe2x80x9d include, for example, a 5- to 14-membered (preferably 5- to 10-membered) (monocyclic or bicyclic) heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms. Concretely mentioned are an aromatic heterocyclic group such as 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, etc; and a non-aromatic heterocyclic group such as 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino, etc.
Among these groups, a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms. Concretely mentioned are 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholino, etc.
The xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d are the same as those mentioned above for the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R5.
The xe2x80x9cheterocyclic groupxe2x80x9d may have 1 to 5, preferably 1 to 3 substituents as mentioned above at possible positions of the heterocyclic group and, when the number of substituents is two or more, those substituents may be the same as or different from one another.
The xe2x80x9cC1-6 alkylxe2x80x9d for R6 includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
The xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d for R7 include, for example, the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d for R5 above, respectively.
The xe2x80x9c1,3-azole compoundxe2x80x9d of the xe2x80x9c1,3-azole compound substituted on the 4- or 5-position, or both, by a pyridyl which may be substitutedxe2x80x9d in the above compound (I) includes, for example, 1,3-thiazole, 1,3-oxazole, 1,3-imidazole, and so forth.
The xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9cpyridyl which may be substitutedxe2x80x9d in the xe2x80x9c1,3-azole compound substituted on the 4- or 5-position, or both, by a pyridyl which may be substitutedxe2x80x9d are, for example, the same as those mentioned above for the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R5.
The xe2x80x9cpyridylxe2x80x9d may have 1 to 5, preferably 1 to 3 substituents as mentioned above at possible positions thereof and, when the number of substituents is two or more, those substituents may be the same as or different from one another. The ring-constituting nitrogen atom in the xe2x80x9cpyridylxe2x80x9d may be oxidized (N-oxidized).
The above-mentioned xe2x80x9c1,3-azole compound substituted on the 4- or 5-position, or both, by a pyridyl which may be substitutedxe2x80x9d may further have 1 to 4, preferably 1 to 3 substituents. When the number of substituents is two or more, those substituents may be the same as or different from one another.
Such xe2x80x9csubstituentsxe2x80x9d include, for example, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, amino which may be substituted, acyl, and so forth.
The above-mentioned xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d includes, for example, the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d for R5 above, respectively.
The above-mentioned xe2x80x9camino which may be substitutedxe2x80x9d includes, for example, (1) an amino which may be substituted by 1 or 2 substituents and (2) a cyclic amino which may be substituted.
The xe2x80x9csubstituentsxe2x80x9d of the above (1) xe2x80x9camino which may be substituted by 1 or 2 substituentsxe2x80x9d include, for example, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, acyl, alkylidene which may be substituted, and so forth. The xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d include, for example, the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d for R5 above, respectively.
The above-mentioned xe2x80x9calkylidenexe2x80x9d of the xe2x80x9calkylidene which may be substitutedxe2x80x9d include, for example, C1-6 alkylidene such as methylidene, ethylidene, propylidene, etc. The xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9calkylidene which may be substitutedxe2x80x9d includes, for example, the same as those mentioned above for the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R5. The number of such substituent is 1 to 5, preferably 1 to 3.
When the number of substituents of the above xe2x80x9camino which may be substituted by 1 or 2 substituentsxe2x80x9d is two, those substituents may be the same as or different from one another.
The xe2x80x9ccyclic aminoxe2x80x9d of the above-mentioned (2) xe2x80x9ccyclic amino which may be substitutedxe2x80x9d includes, for example, 5- to 7-membered non-aromatic cyclic amino optionally containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms and at least one nitrogen atom, such as pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, tetrahydroazepin-1-yl, imidazolidin-1-yl, 2,3-dihydro-1H-imidazol-1-yl, tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl, 3,4-dihydro-1(2H)-pyrimidinyl, etc. The xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9ccyclic amino which may be substitutedxe2x80x9d include, for example, 1 to 3 of the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9c5- to 7-membered saturated cyclic amino which may be substitutedxe2x80x9d described in detail in the foregoing referring to the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R5.
Examples of the 5- to 7-membered non-aromatic cyclic amino substituted by an oxo are 2-oxoimidazolidin-1-yl, 2-oxo-2,3-dihydro-1H-imidazol-1-yl, 2-oxotetrahydro-1(2H)-pyrimidinyl, 2-oxo-3,6-dihydro-1(2H)-pyrimidinyl, 2-oxo-3,4-dihydro-1(2H)-pyrimidinyl, etc.
Preferable example of compound (I) is compound (Ia).
The ring-constituting nitrogen atom in the 1,3-azole in compound (Ia) may be oxidized (N-oxidized).
The xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d and the xe2x80x9camino which may be substitutedxe2x80x9d for R1, include, for example, the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d and the xe2x80x9camino which may be substitutedxe2x80x9d which the above compound (I) may have, respectively.
R1 is preferably an amino which may be substituted. More preferred is an amino which may be substituted by 1 or 2 acyl of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5, xe2x80x94(Cxe2x95x90O)xe2x80x94OR5, xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6, xe2x80x94(Cxe2x95x90S)xe2x80x94NHR5 or xe2x80x94SO2xe2x80x94R7 (more preferably, xe2x80x94(Cxe2x95x90O)xe2x80x94R5 or xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6) wherein each symbol is as defined above. Among others, especially preferred is a 5- to 7-membered non-aromatic cyclic amino optionally containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms and at least one nitrogen atom, which may be substituted by 1 to 3 substituents selected from the group consisting of C1-6 alkyl, C6-14 aryl, C1-6 alkyl-carbonyl, 5- to 10-membered aromatic heterocyclic group and oxo.
The xe2x80x9cpyridyl which may be substitutedxe2x80x9d for R2 or R3 includes, for example, the xe2x80x9cpyridyl which may be substitutedxe2x80x9d which the above compound (I) has.
The xe2x80x9caromatic hydrocarbon groupxe2x80x9d of the xe2x80x9caromatic hydrocarbon group which may be substitutedxe2x80x9d for R2 or R3 includes, for example, a C6-14 monocyclic or fused polycyclic (e.g., bi- or tri-cyclic) aromatic hydrocarbon group, etc. Concretely mentioned is C6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.
The xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic hydrocarbon group which may be substitutedxe2x80x9d include, for example, the same as those mentioned above for the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R5. The number of such substituent is 1 to 5, preferably 1 to 3. When the number of substituents is two or more, those substituents may be the same as or different from one another. The two substituents (preferably alkyl groups) can form, together with a neighboring substituent, a 4- to 7-membered (preferably, 5-membered) non-aromatic carbocyclic ring.
It is preferred that at least one of R2 and R3 is a pyridyl which may be substituted or an aromatic hydrocarbon group which may be substituted, and the other is a pyridyl which may be substituted.
R2 is preferably a pyridyl which may be substituted.
R3 is preferably a C6-14 (preferably C6-10) aryl which may be substituted.
The xe2x80x9csulfur atom which may be oxidizedxe2x80x9d for X includes S, SO and SO2.
The xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R4 includes, for example, the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R5 above.
X is preferably a sulfur atom which may be oxidized. More preferred is S.
In compound (Ia), preferred is a compound wherein
R1 is an amino which may be substituted, preferably a monoacylamino;
at least one of R2 and R3 is a pyridyl which may be substituted or an aromatic hydrocarbon group which may be substituted, and the other is a pyridyl which may be substituted; and
X is S.
More preferred is a compound wherein
R1 is an amino which may be substituted by 1 or 2 acyl of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5 or xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6 wherein each symbol is as defined above;
R2 is a pyridyl which may be substituted by 1 to 5 C1-6 alkyl;
R3 is a C6-14 aryl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy and carboxy; and
X is S.
Another preferred example is a compound, wherein
R1 is
(i) a C1-8 alkyl; C3-6 cycloalkyl or C6-14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, optionally halogenated C1-6 alkyl, carboxy C2-6 alkenyl, optionally halogenated C1-6 alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkoxy, hydroxy, amino, mono-C1-6 alkylamino, carboxy, C1-6 alkoxy-carbonyl, mono-C1-6 alkyl-carbamoyl and C6-14 aryl-carbonylamino,
(ii) a 5-membered heterocyclic group,
(iii) an amino which may be substituted by 1 or 2 substituents selected from the group consisting of (1) C1-6 alkyl,(2) C6-14 aryl, (3) C7-16 aralkyl, (4) 6-membered heterocyclic group, (5) a C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C1-6 alkyl-carbamoyl or 5- or 6-membered heterocycle carbonyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C1-6 alkyl, C1-6 alkoxy, carboxy and C1-6 alkoxy-carbonyl, and (6) di-C1-6 alkylamino-C1-6 alkylidene,
(iv) a 5- or 6-membered non-aromatic cyclic amino which may be substituted by C1-6 alkyl-carbonyl or oxo, or
(v) carboxy;
R2 is a pyridyl which may be substituted by 1 to 3 C1-6 alkyl;
R3 is a C6-10 aryl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, C1-3 alkylenedioxy, optionally halogenated C1-6 alkyl, carboxy C2-6 alkenyl, optionally halogenated C1-8 alkoxy, hydroxy, C7-16 aralkyloxy and C1-6 alkyl-carbonyloxy, and the alkyl group can form, together with the neighboring alkyl group, a 5-membered non-aromatic carbocyclic ring; and
X is S.
More preferred examples of compound (Ia) are
N-[4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]acetamide,
N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,
N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,
N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-2-methylpropionamide,
N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]butyramide,
N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]benzamide,
N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide,
N-[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-Nxe2x80x2-ethylurea,
N-(4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-Nxe2x80x2-propylurea,
4-(4-methoxyphenyl)-2-(2-oxoimidazolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,
4-(4-methoxyphenyl)-2-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-(4-pyridyl)-1,3-thiazole,
4-(4-methoxyphenyl)-2-[2-oxotetrahydro-1(2H)-pyrimidinyl)-5-(4-pyridyl)-1,3-thiazole,
4-(4-methoxyphenyl)-2-(2-oxopyrrolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,
N-[4-(4-ethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,
N-[4-(4-ethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,
N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(3-pyridyl)-1,3-thiazol-2-yl]acetamide,
N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,
N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,
N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]-2-methylpropionamide,
N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]butyramide,
N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]benzamide,
N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide,
N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]-Nxe2x80x2-ethylurea,
N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]-Nxe2x80x2-propylurea,
4-[4-(1,1-dimethylethyl)phenyl]-2-(2-oxoimidazolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,
4-[4-(1,1-dimethylethyl)phenyl]-2-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-(4-pyridyl)-1,3-thiazole,
4-[4-(1,1-dimethylethyl)phenyl]-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]-5-(4-pyridyl)-1,3-thiazole,
4-[4-(1,1-dimethylethyl)phenyl]-2-(2-oxopyrrolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,
N-[4-(3,5-dimethylphenyl)-5-(3-pyridyl)-1,3-thiazol-2-yl]acetamide,
N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,
N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,
N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-2 -methylpropionamide,
N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]butyramide,
N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]benzamide,
N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide,
N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-Nxe2x80x2-ethylurea,
N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]-Nxe2x80x2-propylurea,
4-(3,5-dimethylphenyl)-2-(2-oxoimidazolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,
4-(3,5-dimethylphenyl)-2-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-5-(4-pyridyl)-1,3-thiazole,
4-(3,5-dimethylphenyl)-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]-5-(4-pyridyl)-1,3-thiazole,
4-(3,5-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)-5-(4-pyridyl)-1,3-thiazole,
N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]acetamide,
N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]propionamide,
N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]-2-methylpropionamide,
N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]benzamide,
N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]nicotinamide,
N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]-Nxe2x80x2-ethylurea,
N-[5-(4-pyridyl)-4-(4-trifluoromethylphenyl)-1,3-thiazol-2-yl]-Nxe2x80x2-propylurea, salts thereof, and so forth.
In compound (Ia), compound (Ib) is novel compound.
The xe2x80x9caromatic heterocyclic groupxe2x80x9d of the xe2x80x9caromatic heterocyclic group which may be substitutedxe2x80x9d for R1aincludes, for example, a monovalent group formed by removing an optional hydrogen atom from a 5- to 14-membered preferably 5- to 10-membered (monocyclic, bicyclic or tricyclic) aromatic heterocyclic ring containing 1 to 4 hetero atoms of 1 or 2 species selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, etc. Concretely mentioned are a monovalent group formed by removing an optional hydrogen atom from an aromatic heterocyclic ring such as thiophene, benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, furazan, phenoxazine, etc.; and a ring as formed through condensation of those rings, preferably a monocyclic ring, with one or more, preferably one or two aromatic rings (e.g., benzene ring, etc.), etc.
The preferred example of the xe2x80x9caromatic heterocyclic groupxe2x80x9d is a 5- or 6-membered aromatic heterocyclic group which may be fused with one benzene ring. Concretely mentioned are 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, etc. More preferred are 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 1-indolyl, 2-benzothiazolyl, etc.
The xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9caromatic heterocyclic group which may be substitutedxe2x80x9d and their number are the same as those mentioned above for the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R5.
The xe2x80x9caminoxe2x80x9d of the xe2x80x9camino which may be substituted by substituent(s) selected from the group consisting of a substituted carbonyl and a hydrocarbon group which may be substitutedxe2x80x9d for R1a includes an amino which may be substituted by 1 or 2 substituents selected from the group consisting of a substituted carbonyl and a hydrocarbon group which may be substituted. When the number of substituents is two, those substituents may be the same as or different from one another.
The xe2x80x9csubstituted carbonylxe2x80x9d of the xe2x80x9camino which may be substituted by substituent(s) selected from the group consisting of a substituted carbonyl and a hydrocarbon group which may be substitutedxe2x80x9d includes, for example, a group of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5a, xe2x80x94(Cxe2x95x90O) OR5a or xe2x80x94(Cxe2x95x90O)xe2x80x94NRRaR6a wherein R5a represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, and R6a represents a hydrogen atom or a C1-6 alkyl.
The xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d for R5a include, for example, the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d for R5 above, respectively.
The xe2x80x9cC1-6 alkylxe2x80x9d for R6a includes, for example, the xe2x80x9cC1-6 alkylxe2x80x9d for R6 above.
The examples of the xe2x80x9csubstituted carbonylxe2x80x9d are formyl carboxy, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), C3-6 cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C7-16 aralkyl-carbonyl (e.g., phenylacetyl, 3-phenylpropionyl, etc.), C6-14 aryloxy-carbonyl (e.g., phenoxycarbonyl, etc.), C7-16 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-membered heterocycle carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, etc.), carbamoyl, mono-C1-6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C1-6 alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C6-14 aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), 5- or 6-membered heterocycle carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), etc.
The xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d of the xe2x80x9camino which may be substituted by substituent(s) selected from the group consisting of a substituted carbonyl and a hydrocarbon group which may be substitutedxe2x80x9d for R1a includes, for example, the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R5.
The xe2x80x9ccyclic amino which may be substitutedxe2x80x9d for R1a includes, for example, the xe2x80x9ccyclic amino which may be substitutedxe2x80x9d described in the xe2x80x9camino which may be substitutedxe2x80x9d for R1.
R1a is preferably an amino which may be substituted by substituent(s) selected from the group consisting of a substituted carbonyl and a hydrocarbon group which may be substituted.
The xe2x80x9caromatic hydrocarbon group which may be substitutedxe2x80x9d for R2a includes, for example, the xe2x80x9caromatic hydrocarbon group which may be substitutedxe2x80x9d for R2 or R3 above.
The xe2x80x9cpyridyl which may be substitutedxe2x80x9d for R3a includes, for example, the xe2x80x9cpyridyl which may be substitutedxe2x80x9d which the above compound (I) has.
Preferred example of compound (Ib) is a compound wherein
R1a is an amino which may be substituted by 1 or 2 substituents selected from the group consisting of C1-6 alkyl, C1-6 alkyl-carbonyl, C6-14 aryl-carbonyl and C1-6 alkyl-carbamoyl;
R2a is a phenyl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, optionally halogenated C1-6 alkyl and optionally halogenated C1-6 alkoxy; and
R3a is a pyridyl.
The examples of compound (Ib) are
N-methyl[5-phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]amine,
[5-phenyl-4-(3-pyridyl)thiazol-2-yl]amine,
N-[5-phenyl-4-(3-pyridyl)thiazol-2-yl]acetoamide,
N-[5-[4-(1,1-dimethylethyl)phenyl)-4-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,
N-[5-[4-(1,1-dimethylethyl)phenyl]-4-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,
N-[5-[4-(1,1-dimethylethyl)phenyl]-4-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide,
N-[5-(3,5-dimethylphenyl)-4-(4-pyridyl)-1,3-thiazol-2-yl]acetamide,
N-[5-(3,5-dimethylphenyl)-4-(4-pyridyl)-1,3-thiazol-2-yl]propionamide,
N-[5-(3,5-dimethylphenyl)-4-(4-pyridyl)-1,3-thiazol-2-yl]nicotinamide, salts thereof, and so forth.
A novel compound of the formula: 
wherein R1b represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an amino which may be substituted or an acyl;
R2b represents a N-oxidized pyridyl which may be substituted; and
R3b represents a hydrogen atom, a pyridyl which may be substituted or an aromatic hydrocarbon group which may be substituted; or a salt thereof, [hereinafter sometimes referred to briefly as compound (Ic)] is also within a scope of compound (Ia).
The xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d the xe2x80x9camino which may be substitutedxe2x80x9d and the xe2x80x9cacylxe2x80x9d for R1b include, for example, the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d the xe2x80x9cheterocyclic group which may be substitutedxe2x80x9d the xe2x80x9camino which may be substitutedxe2x80x9d and the xe2x80x9cacylxe2x80x9d for R1 above, respectively.
R1b is preferably an amino which may be substituted. More preferred is an amino which may be substituted by 1 or 2 acyl of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5, xe2x80x94(Cxe2x95x90O)xe2x80x94OR5, xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6, xe2x80x94(Cxe2x95x90S)xe2x80x94NHR5 or xe2x80x94SO2xe2x80x94R7 (more preferably, xe2x80x94(Cxe2x95x90O)xe2x80x94R5 or xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6) wherein each symbol is as defined above.
The xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9cN-oxidized pyridyl which may be substitutedxe2x80x9d are the same as those mentioned above for the xe2x80x9csubstituentsxe2x80x9d of the xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d for R5 above. The xe2x80x9cN-oxidized pyridylxe2x80x9d may have 1 to 4, preferably 1 to 3 substituents as mentioned above at possible positions of the pyridyl and, when the number of substituents is two or more, those substituents may be the same as or different from one another.
The xe2x80x9cpyridyl which may be substitutedxe2x80x9d and the xe2x80x9caromatic hydrocarbon group which may be substitutedxe2x80x9d for R3b include, for example, the xe2x80x9cpyridyl which may be substitutedxe2x80x9d and the xe2x80x9caromatic hydrocarbon group which may be substitutedxe2x80x9d for R3 above, respectively.
R3b is preferably a C6-14 (preferably C6-10) aryl which may be substituted.
A perferred example of compound (Ic) is a compound wherein
R1b is an amino which may be substituted by 1 or 2 acyl of the formula: xe2x80x94(Cxe2x95x90O)xe2x80x94R5 or xe2x80x94(Cxe2x95x90O)xe2x80x94NR5R6 wherein each symbol is as defined above;
R2b is a N-oxidized pyridyl which may be substituted by 1 to 3 C1-6 alkyl; and
R3b is a C6-10 aryl which may be substituted by 1 to 5 substituents selected from the group consisting of halogen atoms, optionally halogenated C1-6 alkyl, optionally halogenated C1-6 alkoxy and carboxy.
The examples of compound (Ic) are
3-[2-acetylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-acetylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-(4-methoxyphenyl)-2-propionylamino-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-(4-methoxyphenyl)-2-(2-methylpropionyl)amino-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-butyrylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-benzoylamino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-(4-methoxyphenyl)-2-nicotinoylamino-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-(Nxe2x80x2-ethylureido)-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-(4-methoxyphenyl)-2-(Nxe2x80x2-propylureido)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-acetylamino-4-(4-ethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-(4-ethylphenyl)-2-propionylamino-1,3-thiazol-5-yl]pyridine 1-oxide,
3-[2-acetylamino-4-[4-(1,1-dimethylethyl)phenyl]-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-acetylamino-4-[4-(1,1-dimethylethyl)phenyl]-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-[4-(1,1-dimethylethyl)phenyl]-2-propionylamino-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-[4-(1,1-dimethylethyl)phenyl]-2-(2-methylpropionyl)amino-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-butyrylamino-4-[4-(1,1-dimethylethyl)phenyl]-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-benzoylamino-4-[4-(1,1-dimethylethyl)phenyl]-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-[4-(1,1-dimethylethyl)phenyl]-2-nicotinoylamino-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-[4-(1,1-dimethylethyl)phenyl]-2-(Nxe2x80x2-ethylureido)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-4-(1,1-dimethylethyl)phenyl]-2-(Nxe2x80x2-propylureido)-1,3-thiazol-5-yl]pyridine 1-oxide,
3-[2-acetylamino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-acetylamino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-(3,5-dimethylphenyl)-2-propionylamino-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-(3,5-dimethylphenyl)-2-(2-methylpropionyl)amino-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-butyrylamino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-benzoylamino-4-(3,5-dimethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-(3,5-dimethylphenyl)-2-nicotinoylamino-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[4-(3,5-dimethylphenyl)-2-(Nxe2x80x2-ethylureido)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-(4-(3,5-dimethylphenyl)-2-(Nxe2x80x2-propylureido)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-acetylamino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-propionylamino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-(2-methylpropionyl)amino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-butyrylamino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-benzoylamino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-nicotionylamino-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-(Nxe2x80x2-ethylureido)-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide,
4-[2-(Nxe2x80x2-propylureido)-4-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]pyridine 1-oxide, and so forth.
Salts of compound (I), compound (Ia), compound (Ib) or compound (Ic) include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Preferred examples of metal salts include alkali metal salts such as sodium salts, potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts; aluminium salts, etc. Preferred examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, etc. Preferred examples of salts with inorganic acids include hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, etc. Preferred examples of salts with organic acids include formates, acetates, trifluoroacetates, fumarates, oxalates, tartrates, maleates, citrates, succinates, malates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc. Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Preferred examples of salts with acidic amino acids include aspartates, glutamates, etc.
Among others, more preferred are pharmaceutically acceptable salts. For example, for the compound having an acidic functional group in the molecule, mentioned are their inorganic salts, such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), and alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.), ammonium salts, etc.; and for the compound having a basic functional group in the molecule, mentioned are their inorganic salts such as hydrobromides, nitrates, sulfates, phosphates, etc., and organic salts such as acetates maleates, fumarates, succinates, citrates, tartrates, methanesulfonates, p-toluenesulfonates, etc.
Process for producing compound (I) (including compounds (Ia), (Ib) and (Ic)) is mentioned below.
Compound (I) can be produced in any per se known manner, for example, according to the methods of the following processes 1 to 3 or analogous methods thereto as well as the methods disclosed in WO 95/13067 or analogous methods thereto in case that compound (I) is 1,3-oxazole compounds, the methods disclosed in U.S. Pat. No. 3,940,486, WO 88/01169, WO 93/14081, WO 95/02591, WO 97/12876 or analogous methods thereto in case that compound (I) is 1,3-imidazole compounds, and the methods disclosed in JP-A-60-58981, JP-A-61-10580, JP-A-7-503023, WO 93/15071, DE-A-3601411, JP-A-5-70446 or analogous methods thereto in case that compound (I) is 1,3-thiazole.
Each symbol in the compounds in the following processes 1 to 3 is same as defined above. The compounds described in the following processes include their salts. For their salts, for example, referred to are the same as the salts of compound (I).
Process 1
Compounds (II), (III), (V), (VII), (XI), (XIII) and (XIV) may be purchased from commercial sources if they are available on the market or can be produced in any per se known manner.
Compound (IV) is produced by subjecting compound (II) to condensation with compound (III) in the presence of a base.
In compound (III), R8 represents, for example, (i) C1-6 alkoxy (e.g., methoxy, ethoxy, etc.), (ii) di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, etc.), (iii) N-C6-10 aryl-N-C1-6 alkylamino (e.g., N-phenyl-N-methylamino, etc.), (iv) 3- to 7-membered cyclic amino 15 (e.g., pyrrolidino, morpholino, methylaziridin-1-yl, etc.) which may be substituted by C6-10 aryl and/or C1-6 alkyl, etc.
The amount of compound (III) to be used is 0.5 to 3.0 mols or so, preferably 0.8 to 2.0 mols or so, relative to one mol of compound (II).
The amount of the base to be used is 1.0 to 30 mols or so, preferably 1.0 to 10 mols or so, relative to one mol of compound (II).
The xe2x80x9cbasexe2x80x9d includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; inorganic bases such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such aspyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, water, and mixtures of those solvents.
The reaction temperature is generally xe2x88x925 to 200xc2x0 C. or so, preferably 5 to 150xc2x0 C. or so. The reaction time is generally about 5 minutes to 72 hours, preferably about 0.5 to 30 hours.
The product as produced in the manner mentioned above may be applied to the next reaction while it is still crude in the reaction mixture, or may be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
Compound (VIII) is produced by treating compound (IV) with an acid.
The amount of the acid to be used is 1.0 to 100 mols or so, preferably 1.0 to 30 mols or so, relative to one mol of compound (IV).
The xe2x80x9cacidsxe2x80x9d include, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
This reaction is advantageously carried out in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Preferred are water, mixtures of water and amides, mixtures of water and alcohols, etc.
The reaction temperature is generally 20 to 200xc2x0 C. or so, preferably 60 to 150xc2x0 C. or so. The reaction time is generally about 30 minutes to 72 hours, preferably about 1 to 30 hours.
The product as produced in the manner mentioned above may be applied to the next reaction while it is still crude in the reaction mixture, or may be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
Compound (VIII) is also produced by treating compound (V) with a base followed by subjecting the resultant compound (VI) to condensation with compound (VII).
In compound (VI), M represents, for example, an alkali metal such as lithium, sodium, potassium, etc.
In compound (VII), R9 represents, for example, same as those mentioned above for R8.
The amount of the base to be used is 1.0 to 30 mols or so, preferably 1.0 to 10 mols or so, relative to one mol of compound (V).
The xe2x80x9cbasexe2x80x9d includes, for example, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Preferred are aliphatic hydrocarbons, aromatic. hydrocarbons, ethers, and mixtures of those solvents.
The reaction temperature is generally xe2x88x9278 to 60xc2x0 C. or so, preferably xe2x88x9278 to 20xc2x0 C. or so. The reaction time is generally about 5 minutes to 24 hours, preferably about 0.5 to 3 hours.
The product as produced in the manner mentioned above may be applied to the next reaction while it is still crude in the reaction mixture, or may be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
Compound (IX) is produced by treating compound (VIII) with a halogen. If desired, this reaction is carried out in the presence of a base or a basic salt.
The amount of the halogen to be used is 1.0 to 5.0 mols or so, preferably 1.0 to 2.0 mols or so, relative to one mol of compound (VIII).
The xe2x80x9chalogenxe2x80x9d includes, for example, bromine, chlorine, iodine, etc.
The amount of the base to be used is 1.0 to 10.0 mols or so, preferably 1.0 to 3.0 mols or so, relative to one mol of compound (VIII).
The xe2x80x9cbasexe2x80x9d includes, for example, aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.
The amount of the basic salt to be used is 1.0 to 10.0 mols or so, preferably 1.0 to 3.0 mols or so, relative to one mol of compound (VIII).
The xe2x80x9cbasic saltxe2x80x9d includes, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium acetate, potassium acetate, etc.
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Preferred are ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitrites, sulfoxides, organic acids, aromatic amines and mixtures of those solvents.
The reaction temperature is xe2x88x9220 to 150xc2x0 C. or so, preferably 0 to 100xc2x0 C. or so. The reaction time is generally 5 minutes to 24 hours, preferably about 10 minutes to 5 hours.
The product as produced in the manner mentioned above may be applied to the next reaction while it is still crude in the reaction mixture, or may be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
Compound (Ia) is produced by subjecting compound (IX) to condensation with compound (X). If desired, this reaction is carried out in the presence of a base or a basic salt.
In compound (IX), Hal represents halogens.
Compound (X) may be purchased from commercial sources if they are available on the market or can be produced according to any per se known methods or analogous methods thereto as well as the methods disclosed in the following process 2.
The amount of compound (X) to be used is 0.5 to 3.0 mols or so, preferably 0.8 to 2.0 mols or so, relative to one mol of compound (IX).
The amount of the base to be used is 1.0 to 30 mols or so, preferably 1.0 to 10 mols or so, relative to one mol of compound (IX).
The xe2x80x9cbasexe2x80x9d includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, nitrites and mixtures of those solvents.
The reaction temperature is xe2x88x925 to 200xc2x0 C. or so, preferably 5 to 150xc2x0 C. or so. The reaction time is generally 5 minutes to 72 hours, preferably about 0.5 to 30 hours.
The product as produced in the manner mentioned above may be applied to the next reaction while it is still crude in the reaction mixture, or may be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
Process 2
Compound (XII) is produced by subjecting compound (XI) to condensation with an amine of the formula: R11H.
R11 represents the xe2x80x9camine which may be substitutedxe2x80x9d for R1 above.
In compound (XI), R10 represents an alkoxy. The xe2x80x9calkoxyxe2x80x9d includes, for example, a C1-6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.
The amount of the xe2x80x9caminexe2x80x9d to be used is 1.0 to 30 mols or so, preferably 1.0 to 10 mols or so, relative to one mol of compound (XI).
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with.
Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols, nitrites, ketones and mixtures-of those solvents. The reaction temperature is xe2x88x925 to 200xc2x0 C. or so, preferably 5 to 120xc2x0 C. or so. The reaction time is generally 5 minutes to 72 hours, preferably about 0.5 to 30 hours.
The product as produced in the manner mentioned above may be applied to the next reaction while it is still crude in the reaction mixture, or may be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
Compound (X) is produced by subjecting compound (XII) to hydrolysis using an acid or a base.
The amount of the xe2x80x9cacidxe2x80x9d or xe2x80x9cbasexe2x80x9d to be used is 0.1 to 50 mols or so, preferably 1 to 20 mols or so, relative to one mol of compound (XII), respectively.
The xe2x80x9cacidxe2x80x9d includes, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc; Lewis acids such as boron trichloride, boron tribromide, etc; thiols or sulfides in combination with Lewis acids; organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, etc.
The xe2x80x9cbasexe2x80x9d includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc; organic bases such as triethylamine, imidazole, formamidine, etc.
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Preferred are alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, sulfoxides, water and mixtures of those solvents.
The reaction time is generally 10 minutes to 50 hours, preferably about 30 minutes to 12 hours. The reaction temperature is 0 to 200xc2x0 C. or so, preferably 20 to 120xc2x0 C. or so.
Compound (X) is also produced by treating compound (XIII) with a hydrogen sulfide in the presence of a base.
The amount of the hydrogen sulfide to be used is 1 to 30 mols or so, relative to one mol of compound (XIII).
The amount of the xe2x80x9cbasexe2x80x9d to be used is 1.0 to 30 mols or so, preferably 1.0 to 10 mols or so, relative to one mol of compound (XIII).
The xe2x80x9cbasexe2x80x9d includes, for example, aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is. no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, aromatic amines and mixtures of those solvents.
This reaction is carried out under atmospheric pressure or pressurized condition. The reaction temperature is xe2x88x9220 to 80xc2x0 C. or so, preferably xe2x88x9210 to 30xc2x0 C. or so. The reaction time is generally 5 minutes to 72 hours, preferably about 0.5 to 30 hours.
The product as produced in the manner mentioned above may be applied to the next reaction while it is still crude in the reaction mixture, or may be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
Compound (X) is also produced by treating compound (XIV) with a phosphorous pentasulfide or Lawesson""s reagent.
The amount of the xe2x80x9cphosphorous pentasulfidexe2x80x9d or xe2x80x9cLawesson""s reagentxe2x80x9d to be used is 0.5 to 10 mols or so, preferably 0.5 to 3 mols or so, relative to one mol of compound (XIV).
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Preferred are ethers, aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons and mixtures of n those solvents.
The reaction time is generally 10 minutes to 50 hours, preferably about 30 minutes to 12 hours. The reaction temperature is 0 to 150xc2x0 C. or so, preferably 20 to 120xc2x0 C. or so.
The product (X) may be applied to the next reaction while it is still crude in the reaction mixture, or may be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
In case that compound (Ia) is an acylamino derivative, the desired product can be also obtained by subjecting the corresponded amine compound to any per se known acylation method.
For example, compound (Ia) wherein R1 is an acylamino which may be substituted is produced by reacting a corresponding 2-thiazolyl amine with an acylating agent optionally in the presence of a base or an acid.
The amount of the xe2x80x9cacylating agentxe2x80x9d to be used is 1.0 to 5.0 mols or so, preferably 1.0 to 2.0 mols or so, relative to one mol of compound (Ia).
The xe2x80x9cacylating agentxe2x80x9d includes, for example, carboxylic acid or a reactive derivative thereof (e.g., acid halides, acid anhydrides, esters, etc.) corresponding to the desired product.
The amount of the xe2x80x9cbasexe2x80x9d or xe2x80x9cacidxe2x80x9d to be used is 0.8 to 5.0 mols or so, preferably 1.0 to 2.0 mols or so, relative to one mol of compound (Ia).
The xe2x80x9cbasexe2x80x9d includes, for example, triethylamine, pyridine, N,N-dimethylamino pyridine, etc.
The xe2x80x9cacidxe2x80x9d includes, for example, methanesulfonic acid, p-toluenesulfonic acid, camphor-sulfonic acid etc.
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Preferred are ethers, aromatic hydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons, nitrites, sulfoxides, aromatic amines and mixtures of those solvents.
The reaction temperature is xe2x88x9220 to 150xc2x0 C. or so, preferably 0 to 100xc2x0 C. or so. The reaction time is generally 5 minutes to 24 hours, preferably about 10 minutes to 5 hours.
The product may be applied to the next reaction while it is still crude in the reaction mixture, or may be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
Compound (Ic) can be also produced according to the methods of the following process 3 or analogous methods thereto.
Process 3
Compound (XV) can be produced according to any per se known methods or analogous methods thereto.
Compound (Ic) is produced by treating compound (XV) with a peroxy acid.
In compound (XV), R2bxe2x80x2 represents a pyridyl which may be substituted. The xe2x80x9cpyridyl which may be substitutedxe2x80x9d includes, for example, the xe2x80x9cpyridyl which may be substitutedxe2x80x9d for R2 above.
The amount of the xe2x80x9cperoxy acidxe2x80x9d to be used is 0.8 to 10 mols or so, preferably 1.0 to 3.0 mols or so, relative to one mol of compound (XV).
The xe2x80x9cperoxy acidxe2x80x9d includes, for example, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, etc.
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitriles, ketones and mixtures of those solvents.
The reaction temperature is xe2x88x9220 to 130xc2x0 C. or so, preferably 0 to 100xc2x0 C. or so. The reaction time is generally 5 minutes to 72 hours, preferably about 0.5 to 12 hours.
Compound (Ic) is also produced by treating compound (XV) with a hydrogen peroxide or an alkylhydroperoxide, in the presence of a base, an acid or a metal oxide if desired.
The amount of the xe2x80x9chydrogen peroxidexe2x80x9d or the xe2x80x9calkylhydroperoxidexe2x80x9d to be used is 0.8 to 10 mols or so, preferably 1.0 to 3.0 mols or so, relative to one mol of compound (XV).
The xe2x80x9calkylhydroperoxidexe2x80x9d includes, for example, tert-butylhydroperoxide, cumene hydroperoxide, etc.
The amount of the xe2x80x9cbasexe2x80x9d the xe2x80x9cacidxe2x80x9d or the xe2x80x9cmetal oxidesxe2x80x9d to be used is 0.1 to 30 mols or so, preferably 0.8 to 5 mols or so, relative to one mol of compound (XV).
The xe2x80x9cbasexe2x80x9d includes, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate and potassium carbonate, etc.
The xe2x80x9cacidxe2x80x9d includes, for example, mineral acids such as hydrochloric acid, sulfuric acid and perchloric acid, Lewis acids such as boron trifluoride and aluminum (III) chloride, titanium(IV) chloride, organic acids such as formic acid and acetic acid, etc.
The xe2x80x9cmetal oxidesxe2x80x9d includes, for example, vanadium oxide (V2O5), osmium oxide (OSO4), tungsten oxide (WO3), molybdenum oxide (MoO3), selenium oxide (SeO2), chromium oxide (CrO3), etc.
This reaction is advantageously carried out in the absence of a solvent or in an inert solvent. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Preferred are halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, organic acids, ethers, amides, sulfoxides, alcohols, nitrites, ketones and mixtures of those solvents.
The reaction temperature is xe2x88x9220 to 130xc2x0 C. or so, preferably 0 to 100xc2x0 C. or so. The reaction time is generally 5 minutes to 72 hours, preferably about 0.5 to 12 hours.
The product may be applied to the next reaction while it is still crude in the reaction mixture, or may be isolated from the reaction mixture in any ordinary manner. This can be easily purified through separation means such as recrystallization, distillation, chromatography and the like.
In the above-mentioned reactions where the starting compounds are substituted by any of amino, carboxy or hydroxy, those groups may be protected by ordinary protective groups which are generally used in peptide chemistry. The protective groups may be removed after the reaction to give the desired products.
The amino-protecting group includes, for example, formyl, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.) which may be substituted, phenylcarbonyl which may be substituted, C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.) which may be substituted, phenyloxycarbonyl which may be substituted, C7-10 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.) which may be substituted, trityl which may be substituted, phthaloyl which may be substituted, etc. These substituents include, for example, halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl, etc.), nitro, etc. The number of those substituents is 1 to 3.
The carboxy-protecting group includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.) which may be substituted, phenyl which may be substituted, trityl which may be substituted, silyl which may be substituted, etc. These substituents include, for example, halogen atoms (e.g., fluoro, chloro, bromo, iodo, etc.), formyl, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, butylcarbonyl, etc.), nitro, C1-6 alkyl (e.g., methyl, ethyl, tert-butyl, etc.), C6-10 aryl (e.g., phenyl, naphthyl, etc.), etc. The number of those substituents is 1 to 3.
The hydroxy-protecting group includes, for example, C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.) which may be substituted, phenyl which may be substituted, C7-11 aralkyl (e.g., benzyl, etc.) which may be substituted, formyl which may be substituted, C1-6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.) which may be substituted, phenyloxycarbonyl which may be substituted, C7-11 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.) which may be substituted, tetrahydropyranyl which may be substituted, tetrahydrofuranyl which may be substituted, silyl which may be substituted, etc. Those substituents include, for example, halogen atoms (e.g., fluoro, chloro, bromo, lodo, etc.), C1-6 alkyl (e.g., methyl, ethyl, tert-butyl, etc.), C7-11 aralkyl (e.g., benzyl, etc.), C6-10 aryl(e.g., phenyl, naphthyl, etc.), nitro, etc. The number of those substituents is 1 to 4.
Those protective groups may be removed by any per se known methods or analogous methods thereto, such as methods using acids, bases, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.; and reduction, etc.
In any case, products formed in the reaction mixtures may be subjected to deprotection, acylation, alkylation, hydrogenation, oxidation, reduction, chain extension, substituents-exchange reaction and combined reactions thereof, to obtain compound (I). These methods include, for example, the methods described in xe2x80x9cShin Jikken Kagaku Kouza (New Edition of Lectures of Experimental Chemistry)xe2x80x9d 14, 15 (1977) edited by Maruzen.
The above xe2x80x9calcoholsxe2x80x9d include, for example, methanol, ethanol, propanol, isopropanol, tert-butanol, etc.
The above xe2x80x9cethersxe2x80x9d include, for example, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.
The above xe2x80x9chalogenated hydrocarbonsxe2x80x9d include, for example, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, etc.
The above xe2x80x9caliphatic hydrocarbonsxe2x80x9d include, for example, hexane, pentane, cyclohexane, etc.
The above xe2x80x9caromatic hydrocarbonsxe2x80x9d include, for example, benzene, toluene, xylene, chlorobenzene, etc.
The above xe2x80x9caromatic aminesxe2x80x9d include, for example, pyridine, lutidine, quinoline, etc.
The above xe2x80x9camidesxe2x80x9d include, for example, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, etc.
The above xe2x80x9cketonesxe2x80x9d include, for example, acetone, methyl ethyl ketone, etc.
The above xe2x80x9csulfoxidesxe2x80x9d include, for example, dimethylsulfoxide, etc.
The above xe2x80x9cnitritesxe2x80x9d include, for example, acetonitrile, propionitrile, etc.
The above xe2x80x9corganic acidsxe2x80x9d include, for example, acetic acid, propionic acid, trifluoroacetic acid, etc.
Where the products are formed in their free form in the reaction, they may be converted into their salts in any ordinary manner. Where they are formed in the form of their salts, they may be converted into free compounds or other salts in any ordinary manner. The thus-obtained compound (I) may be isolated and purified from the reaction mixtures through any ordinary means of, for example, trans-solvation, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography and the like.
Where compound (I), (Ia), (Ib) or (Ic) exists in the reaction mixtures in the form of its configurational isomers, diastereomers, conformers or the like, they may be optionally isolated into single isomers through the separation and isolation means mentioned above. Where compound (I), (Ia), (Ib) or (Ic) is in the form of its racemates, they may be resolved into S- and R-forms through any ordinary optical resolution.
Compound (I), (Ia), (Ib) or (Ic) includes stereoisomers, depending on the type of the substituents therein, and both single isomers and mixtures of different isomers are within the scope of the present invention.
Compounds (I), (Ia), (Ib) and (Ic) may be in any form of their hydrates and non-hydrates.
The agent (pharmaceutical composition) of the. present invention comprising compound (I), (Ia), (Ib) or (Ic) shows a high affinity for adenosine receptor, especially for adenosine A3 receptor, while having low toxicity and few side effects. The agent is useful as a safe medicine.
The agent (pharmaceutical composition) of the present invention comprising compound (I), (Ia), (Ib) or (Ic) has a potent antagonistic activity on mammals (e.g., mouse, rat, hamster, rabbit, feline, canine, bovine, sheep, monkey, human, etc.), a good bioavailability upon administration, a good metabolical stability, and therefore, it can be used for preventing and/or treating diseases that may be related to adenosine A3 receptor, for example, asthma, allergosis, inflammation, Addison""s disease, autoallergic hemolytic anemia, Crohn""s disease, psoriasis, rheumatism, diabetes, and so on. Among others, preferred is for asthma, allergosis, etc.
The agent (pharmaceutical composition) of the present invention comprising compound (I), (Ia), (Ib) or (Ic) has low toxicity, and therefore, compound (I), (Ia), (Ib) or (Ic) is, either directly as it is or after having been formulated into pharmaceutical compositions along with pharmaceutically acceptable carriers in any per se known manner, for example, into tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), liquid preparations, injections, suppositories, sustained release preparations, etc., safely administered orally or parenterally (e.g., locally, rectally, intravenously, etc.). In the pharmaceutical composition of the present invention, the amount of compound (I), (Ia), (Ib) or (Ic) is from 0.01 to 100% by weight or so of the total weight of the composition. The dose of the composition varies, depending on the subject to which the composition is administered, the administration route employed, the disorder of the subject, etc. For example, as an adenosine A3 receptor antagonist, oral composition for treating asthma, its dose for adults (body weight ca. 60 kg) may be from 0.1 to 30 mg/kg of body weight or so, preferably from 1 to 20 mg/kg of body weight or so, in terms of the active ingredient of compound (I), (Ia), (Ib) or (Ic), and this may be administered once or several times a day.
Any ordinary organic and inorganic carrier substances that are generally used in formulating medicines are usable as the carriers for formulating the pharmaceutical compositions of the present invention. For example, employable are ordinary excipients, lubricants, binders, disintegrators, etc. for formulating solid preparations; and solvents, solubilizers, suspending agents, isotonizing agents, buffers, soothing agents, etc. for formulating liquid preparations. If desired, further employable are other additives such as preservatives, antioxidants, colorants, sweeteners, absorbents, wetting agents, etc.
The excipients include, for example, lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light silicic anhydride, etc.
The lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc.
The binders include, for example, crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, carboxymethyl cellulose sodium, etc.
The disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc.
The solvents include, for example, water for injections, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc. The solubilizers include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.
The suspending agents include, for example, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.
The isotonizing agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.
The buffers include, for example, liquid buffers of phosphates, acetates, carbonates, citrates, etc.
The soothing agents include, for example, benzyl alcohol, etc.
A The preservatives include, for example, parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
The antioxidants include, for example, sulfites, ascorbic acid, etc.